Management of the patient with rheumatoid arthritis
J.-G. Tebib and P. Miossec
Changing perceptions
Until the early eighties, the treatment of rheumatoid arthritis (RA) was based on the
principle of responding to the damage caused by disease progression at the time when
the damage actually occurred. In this strategy, known as the "pyramid approach", the
physician responded to the patient's worsening condition by initiating a possibly more
effective therapeutic option, always at a late stage in disease progression. As the efficacy
and toxicity of the medications available were poorly known, such a strategy generally
led to inevitable deterioration of the patient's autonomy because the decision to treat
necessarily lagged behind the progress of the disease in spite of the contributions made
by prosthetic surgery (1). In the eighties, three lines of research led to a complete
change in planning the management of RA. Methotrexate was rediscovered as a long-
acting drug and meticulous comparative studies were carried out on the efficacy and
toxicity of all disease-modifying anti-rheumatic drugs (DMARD). They finally
concluded on the supremacy of methotrexate both for controlling flares and for the
prevention of joint destruction (2). A second line of research confirmed the
importance of early diagnosis by demonstrating the rapidity of joint damage at the
very onset of the disease (3) and as a corollary the need for effective, appropriate
treatment started as soon as possible (4). The relative inefficacy of the basic DMARDS
in arresting structural joint destruction finally led to the search for other modes of
treatment. The most immediate option consisted in applying the principles of
synergistic action of different treatments to fight the same entity; an approach which
had yielded encouraging results against cancer or infectious diseases (5). The second
mode of treatment was based on advances in our knowledge of the RA process, in
particular relating to the central role of the pro-inflammatory cytokines, IL-1 and
TNF-a, where specific antagonists demonstrated spectacular effectiveness in arresting not only the inflammatory phenomenon, but also structural joint damage (6).
Today, thanks to such advances, we have a well-grounded vision of the management of an RA patient which takes into account many sociological, clinical, biological and also economic parameters. Integration of these parameters is a complex process but it is at this cost that we can hope to see the natural outcome of RA gradually improve in the coming years.
Patient assessment
Thanks to advances in the knowledge of the disease, we can now plan a specific treatment strategy for a given patient at a given time in his or her disease. This treatment program is worked out on the basis of a certain number of prognostic factors.
RA status
The treatment program varies according to whether the patient is in the early stages of RA or has established or advanced disease. While the aim is always to relieve pain and to ensure the best possible quality of life for the patient, the methods used to reach these objectives differ depending on the RA status. With a patient who is at the onset of disease, the accent is placed on strict control of disease progression. With a patient who already has severe joint damage, our ambition must be maintenance of optimal functional ability. The following stages can be distinguished:
- the patient with early RA: this is considered as chronic inflammatory rheumatism with a duration of more than 6 weeks but less than 3 months. The clinical, biological or radiological profile may not aUow us to classify this rheumatism as being of rheumatoid origin and the current tendency is to disregard its origin and to base treatment simply on potential gravity (see prognostic factors below);
- classic RA: here the rheumatoid origin is established and is based on the ACR criteria (table I) (7) or on later attempts to improve these criteria (8). This diagnostic method concerns patients whose disease has progressed for more than three months and up to two years. In such circumstances, signs of joint damage are frequently observed and must be taken into account when considering the use of DMARDs. These first two groups require treatments which are sufficiently aggressive to arrest disease progression;
-end-stage RA: by calling upon focused treatments, whether infiltrations or orthopaedic surgery, management of these patients must take account of the inflammatory component and in particular of the joint damage which worsens functional status.
Evaluation of patient status at the time he or she is first seen requires specialized
tools for optimal classification and to ensure the most appropriate treatment. These
tools aim at measuring the inflammatory process or disease activity, as well as joint
damage or disease progression. The findings of prospective studies have provided us
with a certain number of prognostic factors.
Table I - The ACR criteria (7) compared with the criteria proposed by Visser etal (8).
ACR criteria
Duration of signs on first examination at least 6 weeks
1
2 3 4
5
6 7
Morning stiffness lasting more than one hour Arthritis of at least 3 joints Arthritis affecting the hand Symmetrical arthritis
Compatible radiological appearance
Rheumatoid nodules Rheumatoid factors
Criteria of Visser et al Duration of signs on first examination
at least 6 weeks and not more than 6 months
1
2 3 4
5
6
Morning stiffness lasting more than one hour
Arthritis of at least 3 joints Bilateral pain on MTS pressure Compatible radiological appearance
Rheumatoid factors
Presence of antifilagrin antibody
The 1987 ACR criteria (7) are compared with Visser's criteria, proposed recently but not yet validated (8).
The latter repeat nearly all the clinical arguments, simplifying the analysis of the joint manifestations while regarding joint pain and not only arthritis as a criterion. A duration of more than 6 weeks which was a requirement for the first 4 criteria of the ACR becomes a criterion in its own right. Finally, Visser at al. take into account the good discriminating value of antifilagrin antibodies.
Disease activity
Clinical and paraclinical measurements make it possible to assess the inflammatory state at a given time and also the response to the treatment.
Clinical scales (9)
These take into account the subjective experience of the patient and the clinical investigations.
Measurement of subjective experience
Several measurements have been proposed and their sensitivity and specificity have
been analysed. Duration of morning stiffness is often poorly quantified by the
patient but can easily be assessed in dinical practice. Stiffness lasting longer than 45 minutes must be regarded as abnormal. Pain is adequately measured by patient self- rating on a 100-mm visual analogue scale; the same method can be used to quantify disability at a given time. Measurements greater than 45 mm must be regarded as abnormal. More accurate but more difficult to carry out in clinical practice, questionnaires such as the Health Assessment Questionnaire (HAQ) are the cornerstone of assessment of subjective experience in all therapeutic trials.
Simplified forms can be used in clinical practice (table II).
Table II - Follow-up questionnaire for patients with rheumatoid arthritis.
The questions which you are asked will enable us to better know your disease and the effect it has on your daily activity. Please try to answer as accurately as possible, even if some of the questions do not seem to you to correspond exactly to your condition. If you have a problem understanding the questions, the nurse in attendance will be able to help you. Thank you for your collaboration.
Affix patient label here
D a t e : / / Consulting doctor:
• What drugs are you taking at the moment? Refer to your prescription and ask the nurse or receptionist for help if necessary.
Name of drug 1.
2.
3.
4.
5.
6.
7.
Dose Adverse effects
• Tick the box which corresponds best to your present condition.
Today, are you able...
To dress without help, including tying shoelaces and fastening buttons?
To raise a full cup or glass to your mouth?
To walk outside on even ground?
To wash yourself all over and dry yourself?
To bend and pick up an object on the ground?
To use an ordinary water tap?
To get in and out of a car?
without with some any difficulty difficulty
with great incapable of difficulty doing it
a o o
0
o a a
o o a a a a a
0
o a
0
a a a
a a a
D
•
O
0
• How severe do you consider your joint pain has been this week? Indicate severity by putting a cross on the line below, between no pain at all (to the left) and intense pain (to the right).
No pain Unbearable pain
I 1
• When you got up this morning, were your joints stiff?
Yes • No •
If you answered yes, how long did it take for your joints to warm up?
minutes or hours.
' How severe do you consider your rheumatism has been this week? Indicate severity by putting a cross on the line below, between no rheumatism at all (to the left) and severe rheumatism (to the right).
No
rheumatism Unbearable
THIS PART TO BE COMPLETED BY THE MEDICAL TEAM ONLY
JOINT PAIN AND SWELLING COUNT
RIGHT LEFT Pain Swelling Pain Swelling
temporo-mandibular sterno-clavicular acromio-clavicular
shoulder elbow
wrist MCP 1/2/3/4/5 IP(P) 1/2/3/4/5
IPD 2/3/4/5
Hip Knee Ankle Tarsus MTP IP(P) & IPD
Total
t i l l 1 1 1 1
1 1 1
• • • • • •
1 1 1 1 1 1 1 1
1 1 1 1 1 1 1 1 1 1 1
• • • • • •
• • • • • •
1 1 1 1 1 1 1 1
1 1 1 1 1 1 1 1 1 1 1
• • • • • •
1 1 1 1 t i l l
1 1 1 1 1 1 1 1 1 1 1
• • • • • •
1 1 1 1 1 1 1 1
TOTAL PAIN : SWELLING : DAS:
This questionnaire is given to the patient during the consultation. The first part is completed by the patient who reports his or her status by answering a certain number of items: the simplified Health Assessment Questionnaire (HAQ) measures the general status of the patient in daily life. Replies are scored from zero to 3 points depending on the answer selected. A visual analogue scale is proposed to measure pain intensity and also the severity of rheumatism. The second part of the questionnaire is completed by the physician who counts the number of painful and swollen joints. From these results, several indices can be calculated, including the DAS if the ESR is available.
Objective measurement
Examination of the joints remains the keystone of dinical analysis. The number of painful and swollen joints is the usual index. Several methods are used in clinical practice. The simplest method should be used (assessment of 28 joints), but more complete counts exist. In a first clinical approximation, counts higher than 12 for pain and 8 for swelling indicate significant joint activity.
The search for extra-articular manifestations, in particular rheumatoid nodules or Sjogren syndrome, completes this examination which, of course, forms part of a full clinical check-up, during which particular attention must be paid to weight loss.
The contribution of laboratory tests
These serve to confirm the analysis of the activity rather than to provide any decisive information, since in RA the clinical signs are strongly correlated with the inflammatory syndrome. Sometimes, dissociation between biological signs of inflammation and relative clinical latency may suggest that a concomitant disorder should be sought. Measurement of the active phase reactants and in particular of C- reactive protein is very informative. The erythrocyte sedimentation test remains the most usefiil investigation, even if it is only moderately sensitive and above all non- specific. Other laboratory tests are not directly useftil for measurement of disease activity. Thus, immunological tests such as the presence (and a fortiori the quantification) of rheumatoid factors (RF) have no place here.
The contribution of Imaging
Simple radiography is not informative concerning disease activity. More recent techniques such as ultrasonography (10) or magnetic resonance imaging (11) may enable very early diagnosis of arthritis or tenosynovitis. These investigations are not yet current practice.
Disease progression
Assessment of disease progression attempts to measure structural joint damage over time, which depends mainly on the severity of disease flares. Nowadays, it is carried out by quantitative analysis of informative radiographs, primarily of the hands and the feet. Several increasingly sensitive quantification techniques have been proposed as knowledge of joint damage and analytical tools has advanced. Currently, the Sharp van der Heijde count is the most used (12). While it is very sensitive (0 to 348) and reproducible, it is impossible to use in clinical practice because of the time- consuming measurement which separately analyses narrowing and erosion of sensitive sites of the hands and feet.
These measurements of activity and progression help to define RA status at any given time and so to decide on an appropriate treatment option.
Here, the DAS (disease activity score) can prove to be of practical use since it
yields an overall score representative of disease activity (13). It is obtained by
regression studies which retain the most important confounding factors. This yields
a complex formula: DAS ^^ = 0.56 x V (number of painful joints/28) + 0.28 x V
(number of swollen joints/28) + 0.7 x log (VS) + 0.014 x patient assessment of his or her RA state. The higher the score, the greater the disease activity. Briefly, a DAS <
3.2 is considered to indicate low activity, between 3.2 and 5.1 intermediate activity and > 5.1 high activity. However, this index is not very meaningful and its calculation requires an abacus or a programmed calculator. It can also be sufficient to classify disease activity according to the same parameters. Depending on the number of affected joints, RA is defined as moderate (less than 3 affected joints, with arthralgia but without joint damage), active (4 to 12 inflammatory joints, moderate joint damage) or severe (more than 12 inflammatory joints, possibility of extra- articular signs and proven joint damage).
Prognostic factors
Prognostic factors are taken into account in order to develop a therapeutic strategy according to the probable course of the disease. Such an approach requires that the physician should anticipate the course the disease will take in a specific case. During recent decades many studies have addressed this question. Certain results still lack adequate confirmation and the findings of some authors are contradictory. In particular, we are as yet unable to correctly weigh each prognostic factor against the others for a given individual. In spite of these drawbacks, a certain number of decisive factors have to be taken into account.
Socio-epidemiological data
Late onset of the disease or onset in men aged less than 50 years appear to indicate a poor prognosis and RA in the young women is likely to be severe (14,15).
Low socio-economic status and, in particular, low formal education is a very significant unfavourable factor (15).
Characteristics of tlie disease
Persistent or extensive RA of more than 6 months duration, tenosynovial involvement of the hands or the early appearance of rheumatoid nodules are factors of poor prognosis, as is a marked inflammatory syndrome persisting for more than 6 months (14).
Early radiological lesions appearing before 8 months are a sign of severe RA.
Biological markers
HLA-DRl and DR4 antigens indicate a poor prognosis (14). Although the importance of these factors is still debated, homozygosity (DRl/DRl or DR4/DR4) or heterozygosity (DR1/DR4) appear more prejudicial than a single allele of the type DRl/xorDR4/x(15).
The presence of rheumatoid factors marks the most severe RA and its association
with HLA groups further worsens the unfavourable prognosis of this characteristic (16).
Treatments of RA
In the current approach to RA, therapy must be selected according to the state of the disease and in particular according to its prognosis. Some significant points must be stressed:
- All proven cases of RA must benefit from basic treatment appropriate to the disease prognosis, the principal objective being to control flares of activity;
- Global management of the patient is crucial. The cornerstones of management are patient education and surgery as well as the use of sophisticated treatments. These treatments must also take into account the peculiar nature of this disease. It may present spontaneous remissions lasting several years or, on the contrary, can evolve very unfavourably, and treatment will have to be adjusted depending on disease reponse to the strategies undertaken.
Patient education
This addresses significant issues with the sole objective of familiarising the patient with his or her disease and thus achieving better compliance with treatment. The physician must make clear to the patient the rationale for the therapeutic strategy chosen this should be based on a simple explanation of the origin of the disease and available treatments, explaining not only their mode of action but also, in particular, their adverse effects. Such contact can best take place in the course of patient education day courses where the patient will be able to meet various actors in treatment (doctors, nurses, physiotherapists, ergotherapists, etc.).
Symptomatic treatment
This classically includes anti-inflammatory drugs and analgesics. They are regarded today as adjuvant treatments, alleviating symptoms while awaiting the cure broughtby DMARDs. Beside stage II analgesics, morphine and its more convenient derivatives appear today to take a greater place. Anti-cyclooxygenase-2 (anti-COX-2), better tolerated than traditional anti-inflammatory drugs, is a logical option.
However, it has the same renal toxicity and recenthly some contra-indications, must be known.
Algorithm for current use of DMARDs (fig. D
This is the centre of the entire treatment strategy. Briefly, the early management of the
patient, RA with a favourable prognosis and RA with poorer prognosis must all be
considered. Early management may be in accordance with the diagnosis of chronic
inflammatory rheumatism which does not yet have RA status. In the latter case,
hydroxychloroquine or salazopyrine have their place; the first allowing for the
possibility of arthritis in the setting of a lupus disease, and the second for that of
peripheral arthritis belonging to the seronegative spondylarthropathies.
In a patient with inflammatory rheumatism affecting the small joints and presenting signs of severity, synthetic purine or pyrimidine inhibitors should be started, methotrexate being currently used more than leflunomide for historical reasons and because it is equally effective at a more moderate cost. The accepted dose of methotrexate is 7.5 to 20 mg weekly, while 10 to 20 mg daily is the dose suggested for leflunomide. Treatment is adjusted after 4 to 6 weeks according to the effect on the signs of activity, within limits which depend on the duration of disease, the age of the patient and the tolerance, while always attempting to reduce activity as closely as possible to a state of remission. In case of failure it will be necessary to resort to combination therapy, still centred on the nucleotide synthesis inhibitors and methotrexate in particular. At the present time at least four possible combination regimens have been validated:
- methotrexate and cyclosporine (17) have been shown to be more effective through the synergistic action of the two drugs. The suggested dose of cyclosporine is 2.5 mg/kg/day;
Fig. 1 - Algorithm for current use of DMARDS in rheumatoid arthritis.
In the case of chronic proven inflammatory rheumatism, after vasculitis has been ruled out, two situations are possible.
If the clinical profile is that of proven RA (7, 8), then introduction of a DMARD is imperative. The choice of DMARD will be made after assessing the prognosis (15) and methotrexate is still the drug of choice if the disease is potentially severe. If the patient does not respond to this treatment or if this strategy is not effective even with increased doses, its replacement by leflunomide and combination therapies must be considered, which may be conventional or which may include biological treatments (see text). These recommendations are likely to be modified in the future, depending on the findings of current studies on the immediate use of biological treatments in the hope of arresting the RA process at its onset.
If RA is uncertain, the debate will mainly concern the diagnosis of peripheral forms of spondylarthropathies and while waiting for an established diagnosis, salazopyrine can be proposed as it is effective in both diseases.
-methotrexate, salazopyrine, hydroxychloroquine and cortisone (18). This quadruple combination is more effective in terms of control of disease activity and progression than methotrexate alone. Moreover, there is no significant increase in side effects;
-the combination of methotrexate and meflunomide (19) appears to be of interest in inadequate control of RA which is refractory of methotrexate;
- combination therapy with methotrexate and infliximab (20) seems one of the most effective alternatives today. However, the physician must take into consideration the cost of the treatment (approximately 10 000 euros per year). This combination is the only one which after two years demonstrated arrest of structural degradation.
Steroids are less used today than in previous decades because of improved knowledge of the efficacy of DMARDs. However, steroids given in low doses effectively reduce the progression of joint damage (21), without involving significant bone damage if given at less than 10 mg/day. With the exception of some limited indications, steroids are now generally used in association (see above).
Biological treatments, which are recent developments, are the therapeutic application of current knowledge on the imbalance between the production of pro- inflammatory cytokines such as IL-1 or TNF-a and their physiological inhibitors.
These drugs appear very effective in controlling disease activity and reducing progression, but they have the disadvantage of being costly. Considerable efforts are being made to decrease cost through less complex production techniques. Moreover, etanercept (Enbrel) which has recently been authorised in the USA for the treatment of early RA, offers the possibility of using these drugs before joint damage has occurred. However, these new molecules have not yet proven their total safety in the treatment of young patients.
Surgery
The role of surgery has decreased to some extent while patient management has progressed. Prosthetic surgery is still irreplaceable. However, the aim of the current advances in surgery is to prevent the joint destruction which is inevitable once the process has begun.
Adjuvant treatments
Like surgery, the indications of local treatment have significantly decreased. Today, infiltrations and synoviortheses still have a place in the local treatment of a particular joint and form an integral part of overall management of the disease.
Physiotherapy or ergotherapy also belong to the arsenal available to improve the
status of already degraded patients. Along the same lines, protective devices such as
plantar splints aim at reducing the mechanical factor of damage induced by
weakening of the tendon or articular structures secondary to the RA process. As with
surgery, prospective studies of the process of destruction have led to significant
progress in damage prevention, for example by use of suitable plantar ortheses (22).
Follow-up of RA
Follow-up includes regular monitoring of the patient at least twice a year, with more rapid intervention if a flare-up occurs. This implies flexible organisation of the department or clinic and staff who are famiHar with these practice methods. Clinical examination is an essential part of patient surveillance, comparing current and previous results to measure activity intensity and response to the therapeutic regimen. Overall, it can be considered that every patient who presents signs which classify his or her disease as active RA requires reassessment of therapeutic strategy with the aim of arresting joint destruction, which is an overwhelming event (4).
With this goal in mind, the DAS we have presented above can be of value. Thus, an improvement of the score from 0.6 to 1.2 indicates moderate response and improvement > 1.2 a good response, whereas a decrease to < 0.6 shows that treatment is ineffective.
Conclusion
Significant advances have been made in recent decades. They are the consequence of better analysis of the RA process rather than of progress due to discovery of new treatments, even though today we can reasonably have real hope in biological treatments (23).
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